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Wednesday, 26 April 2017

Myc, Models and Tumour Growth

When I wrote the NEATG model of tumour growth, published in
the journal PeerJ (https://peerj.com/articles/2176/),
I focused on the behaviour of individual cells and on the role of cell
competition and cell death in tumour growth. All models have to simplify and
abstract, and the NEATG model does exactly that. The model steered clear of the
molecular basis for the behaviour of the cells – my working assumption was that
cells produce soluble factors and signalling proteins that mediate their
cell-cell and cell-tissue interactions. It was one of the reasons I called the
model NEATG (Non-physiological Evolutionary Algorithm for Tumour Growth – though as Sebastien Benzekry pointed
out to me, the fact that the model has cells and tissues already makes it
fairly physiological… ).

Despite the level of abstraction, the model clearly does show cellular behaviours that mimic aspects of tumour growth and response to
cytotoxic chemotherapy. A surprise for me was that the model showed that accelerated tumour regrowth following
chemotherapy is driven by cell competition and the levels of cell death. I spent time looking at the research literature on these topics and found that my results were actually in line with clinically relevant phenomena – which is what makes the model interesting.

A recent paper from a group of researchers from the
University of Bologna entitled MYC, CellCompetition, and Cell Death in Cancer: The Inseparable Triad (available open access from the journal genes –
it’s well worth a read), casts some interesting light on the topic. C-Myc is
one of the most important of the master genes involved in cell cycle
progression and tissue growth. It’s a transcription factor, which means it
regulates the activity of other genes, and is often switched on permanently in
tumours rather than coming on and off as required. It’s widely associated with
a whole range of different cancers.

In this paper the authors review recent evidence from Drosophilia (fruit fly) models of cancer
and how they are implicated in cell growth, cell death and cell competition.
They outline the way that competition selects for cells that are ‘fittest’ and
that less fit cells are effectively killed off – in just the way that they do
in software in my model. The evidence that they outline suggests that one of
the drivers for the behaviour of these cells is c-Myc, making it an important
component at the physiological level missing from NEATG.The authors themselves make note of the
results from the NEATG model:

Our findings suggest that
CC [cell competition] is an innate process governing both cancer initiation and
progression, where cell death fuels the clonal expansion of the fittest cells
in the context. CC and apoptosis thus appear to be strictly linked one another,
and emerge as fundamental cancer drivers also in a computational model of
tumour growth, where several parameters of malignancy such as intra-tumour
heterogeneity and accelerated repopulation have been taken into account.

For the next stage of work on this model I will be
investigating the metabolic impact of cell growth in tumour growth, and the
impact that cell death has on this. My prediction is that the model will show
that populations of ‘super-feeders’ will emerge during tumour growth – and that
chemotherapy helps to select for these populations of cells. However, as this
stage I don’t really know that that’s what happens – I have to wait and see what
the data tells me…

In the meantime I’ll finish with some final words from the
team at Bologna :

Cells cooperate to
build an organ and, in a similar way, they cooperate to build a cancer.
Although the contexts are impressively distant, MYC-mediated cell competition
seems to be at work in both cases with the same basic, sequential elements:
cell–cell disparity in MYC contents, death of the cells with lower MYC levels,
and proliferation of the cells with higher MYC levels. This stereotypical
module shapes organ development and, possibly, cancer evolution. In growing
tumours, an excess of dying cells is known to contribute to mass expansion, but
the implication of MYC-mediated cell competition in this cancer trait has just
begun to be investigated. Further research is warranted on the intricate “life
and death” signals exchanged by confronting cell populations within the cancer
community.